Aryl substituted - hydroxy substituted cyclohexanecarboxylic acids and esters

ABSTRACT

HYDROXYACIDS AND HYDROXYESTERS OF THE FORMULA:   1-(R-OOC-),2,3-DI(R&#39;&#39;-),4-(HO-),4-AR-CYCLOHEXANE   WHEREIN R IS HYDROGEN OR LOWER ALKYL, R&#39;&#39; IS LOWER ALKYL AND AR IS SUBSTITUTED ARYL, ARE INTERMEDIATES IN THE PREPARATION OF 2-LOWER ALKYL-3-LOWER ALKYL-4-ARCYL-CYCLOHEXENECARBOXYLIC ACIDS AND ESTERS WHICH ARE ACTIVE AGENTS FOR THE SUPPRESSION OF ANIMAL REPRODUCTION.

United States Patent Gfice ABSTRACT OF THE DISCLOSURE Hydroxyacids andhydroxyesters of the formula:

Z QA3 o o R wherein R is hydrogen or lower alkyl, R is lower alkyl andAr is substituted aryl, are intermediates in the prep aration of 2-l0weralkyl-3-lower alkyl 4 arcyl-cyclohexenecarboxylic acids and esters whichare active agents for the suppression of animal reproduction.

The compounds of the present invention are of the formula:

wherein R is hydrogen or lower alkyl of up to 8 carbon atoms, R is loweralkyl of up to 6 carbon atoms and Ar is COOR wherein R is hydrogen,hydroxy, lower alkoxy of up to 4 carbon atoms, lower acyloxy of up tocarbon atoms or tetrahydropyranyl 2 oxy R is hydrogen, hydroxy, loweralkyl of up to 4 carbon atoms, lower alkoxy of up to 4 carbon atoms,lower acyloxy of up to 5 carbon atoms, chlorine, tetrahydropyranyl 2 oxyor trifluoromethyl and R is hydrogen, hydroxy, lower alkyl of up to 4carbon atoms, lower acyloxy of up to 5 carbon atoms, diethylaminoethoxy,thiomethyl, trifluoromethyl, dimethylamino or tetrahydropyranyl-Z-oxy,and wherein at least 1 and not more than 2 of R R and R is hydrogen;3,4-methylenedioxyphenyl, a-naphthyl or ,B-naphthyl.

The compounds of the present invention are prepared by thesaponification of their corresponding lactones or by the reaction of anaryl Grignard reagent or an aryl lithium com-pound and a 2-lower alkyl 3lower alkyl- 4-ketocyclohexanecarboxylic acid. The preparation of thelactones is disclosed in my copending application Ser. No. 662,282 filedcontemporaneously herewith now abandoned. The utilty of the 2-loweralkyl-3-lower alkyl-4- aryl-cyclohexenecarboxylic acids and estersprepared from the compounds of the present invention is fully describedin my copending application Ser. No. 662,311 filed contemporaneouslyherewith.

The preparation of the compounds of the invention is illustrated by thefollowing reaction schemes:

3,567,770 Patented Mar. 2, 1971 and COOH OH COOH ArMgBr(or ArLi) o:

R! R! R, R!

The compounds of the invention are used to prepare the final 2-l0weralkyl-3-lo'wer alkyl-4-aryl-cyclohexenecarboxylic acids and estersaccording to the following reaction scheme:

OE Strong Acid C O O R Ar I 'Ar COOR ArCOOR 1's R I'v 1'1 Typicallactone starting materials for the compounds of the present inventionare the lactones of:

2-methyl-2-ethyl-4-hydroxy-4- (m-anisyl) cyclohexanecarboxylic acid,

2,3-dimethyl-4-hydroxy-4-(m-anisyD- cyclohexanecarboxylic acid,

2,3-diethyl-4-hydoxy-4- (m-anisyl) cyclohexanecarboxylic acid,

2-methy1-3-propyl-4-hydroxy-4- (m-anisyl cyclohexanecarboxylic acid,

2-propyl-3-butyl-4-hydroxy-4-(m-anisyl)- cyclohexanecarboxylic acid,

2,3-dimethyl-4-hydroxy-4-(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2-ethyl-3 -butyl-4-hydroxy-4- 3 ,4-methylenedioxyphenylcyclohexanecarboxylic acid,

2, 3 -diethyl-4-hydroxy-4- (p-trifluoromethylphenylcyclohexanecarboxylic acid,

2, 3 -dibutyl-4-hydroxy-4- (m-trifluoromethylphenyl)cyclohexanecarboxylic acid,

2-methyl-3-propyl-4-hydroxy-4-(o-methoxy-p-acetoxyphenyl)cyclohexanecarboxylic acid,

2-methyl-3 -butyl-4-hydroxy-4- (o,p-diacetoxyphenyl)cyclohexanecarboxylic acid,

The following examples illustrate the preparation of the compounds ofthe invention.

EXAMPLE I 2-methyl-3 -ethyl-4-hydroxy-4- m-ani syl cyclohexanecarboxylicacid A mixture of 10.0 g. of the lactone of 2-methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid, 10.0 g. ofsodium hydroxide, ml. of methanol and 100 ml. of Water is stirred andrefluxed for two hours and is then dilutel with 250 ml. of water andevaporated to remove the methanol. The solution is acidified with dilutehydrochloric acid, and is extracted with ether. The ether solution israpidly washed with water, dried over anhydrous magnesium sulfate andfiltered. The residue is recrystallized from ether to afford2-methyl-3-ethyl-4- hydroxy 4-(m-anisyl)cyclohexanecarboxylic acid; M.P.203204 C.

RA max: 2.83, 5.87 and 5.94 (split, 7.78, 8.03, 10.23,

12.80, 14.27 (KBr) NMR (pyr.): 0.63, 0.75, 0.87; 1.46, 1.57; 2.96

boxylic acid (as prepared in Example XIV) in 260 ml. of methanolcontaining 35 ml. of water and 1.5 ml. of 12 N Example Compound formedM.P., C. U.V. max. (KBr) II 2-methyl-3-ethyl-4-hydroxy-4-(oanisyl)-cyclliexanecarboxylic acid 187-188 2%275872and 5.97 (split),7.74, 8.10,

111' 2-methyl-3-ethyl-4-l1ydroxy-4-(p-thioanisyD-cyclohcxanecarboxylicacid 180-100 2.83, 5.00, 7.00, 10.37, 11.00, 12.20 1.

IV 2-mcthyl-3-cthyl-4-hydroxy-4-(p-tolyl)cyclohcxanecarboxylic acid201-202 2.82, 5.00, 8.10, 10.32, 12.27, 14.10

2-methyl-3-ethyl-4-hydroxy-4-(m-tolyl)cyclohexauecarboxyl 0 acid 154-1552.82, 5.80, 8.01, 8.40, 0.60, 12.78, 13.62 1.2-1nctl1yl-3-cthyl-4-l1ydroxy-4-(p-trifiuoromethylphcnyl)cyclohcxauccarboxylicacid 200-201 2.83, 5.87 and 5.98 (split), 7.50, 8.02,

VII2-mctliyl-3-ethyl-4-hydr0xy-4-(m-trifluoromethylphenyl)cyclohexanccarboxylicaeid 160-170 2.85, 5.83 aiid 5.07 s1plit) ,7.50, 8.60,

VIII2-n1etl1yl-3-etl1yl-4-hydroxy-4-(3,4-methylencdi0xyplienyl)cyclolicxanccarboxylicacid 106-197 2.82, 3.86gand504 (split), 8.00, 0.60,

IX 2-methyl-3-cthyl-4-l1ydroxy-4-(a-naphthyl)-cycl0hexanecarboxylic acid177-178 2.82.6587 and 5.05 (split), 7.70, 10.13,

X. 2-methyl-3-othyl-4-hydroxy-4-(B-naplithyl)-cyclol1exanecarb0xy1icacid 216-217 2.85, 5.00, 8.00, 8.58, 11.67, 12.20, 13.33

XI 2-mcthyl-3-ethyl-4-hydroxy-4-(a-thienyl)-cycloliexanccarboxylic acid164-166 2.823388, 8.02, 9.62, 10.10, 11.70, 14.15,

XII 2-methyl-3-ethyl-4-hydroxy-4-benzylcyclohcxanccarboxylic acid142-143 2.88, 5.84, 8.23, 10.14, 11 51, 13.03, 14 15;;

XIlI 2-metl1yl-3-propyl-4-(p-anisyl)cycloliexanccarboxylic acid 106-1072.84, 5 00, 7.00, 0.57, 11 00, 12.35,.

EXAMPLE XIV 2-methyl-3-ethyl-4-hydroxy-4- (m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of2-methy1-3-ethyl- 4-hydroxy 4 (mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, 10.0 g. of sodiumhydroxide, 100 ml. of methanol and 100 ml. of water is stirred andrefluxed for two hours. It is then diluted with 250 ml. of water andevaporated to remove methanol. The insoluble oily material is removed byextraction with ether and is discarded. 200 ml. of methylene chloride isadded to the solution and the mixture is stirred and is maintained at0-5 C. while making the mixture barely acidic witl cold dilutehydrochloric acid. The methylene chloride phase is separated, washedtwice with brine, dried over anhydrous magnesium sulfate and evaporatedto a residue. The residue is recrystallized from ether to afford2-methyl-3- ethyl-4-hydroxy 4(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, M.P. 149-151C.

0. max: 2.83, 5.88, 8.02, 8.98, 9.61, 10.34, 10.92,. (KBr) NMR (pyr.):0.62, 0.73, 0.85; 1.46, 1.58; 2.95

Folowing the procedure of Example XIV, there are prepared:

EXAMPLE XV 2-methyl-3-ethyl 4hydroxy-4-(o-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid; M.P.164-166 C.

M max.: 2.88, 5.87, 8.13, 10.24, 10.85, 11.52, 13.28 1. (KBr) NMR(pyr.): 0.67, 0.79, 0.90; 1.47, 1.58; 2.97

EXAMPLE XVI 2-methyl 3 ethy l- 4hydroxy-4-(o-methoxy-p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylicacid, M.P. 1 18130 C.

AA max.: 2.86, 5.87, 8.31, 9.62, 10.10, 11.04, 11.92 1.

(KBr) NMR (pyr.): 0.65, 0.76, 0.88; 1.46, 1.57; 2.93

NMR (CDC1 0.67, 0.78, 0.89; 1.02, 1.13; 1.82, 2.57

EXAMPLE XVII 2-methyl-3-ethyl 4hydroxy-(o,p-bis-tetrahydropyranyloxyphenyl)cyclohexanecarboxlic acid,M.P. 100- 108 C. M max.: 2.88, 5.87, 7.99, 9.61, 9.97, 10.38, 10.95,11.85,

11.85;]. (KBr) NMR (pyr.): 0.73, 0.85, 0.96; 1.52, 1.63; 2.98 Calcl. forC H O (percent): C, 67.51; H, 8.28. Found (percent): 67.00; H, 8.33.

EXAMPLE XVIII 2-methyl-3-ethyl-4-hydroxy-4-(m-hydroxyphenyl)-cyclohexanecarboxylic acid A suspension of 10.0 g. of2-methyl-3-ethyl-4-hydroxy- 4 (mtetrahydropyranyloxyphenyl)cyclohexanecar- 0 max.: 2.96, 3.15, 5.78,7.50, 9.60, 10.26, 12.68, 13.31,

14.23,. (KBr) NMR (pyr.): 0.63, 0.74, 0.85; 1.45, 1.57; 2.92

EXAMPLE XIX Z-methyl-3-ethyl-4-hydroxy-4- (o-hydroxyphenyl)cyclohexanecarboxylic acid Following the procedure of Example XVIII, butstarting with 2-methyl 3ethyl-4-hydroxy-4-(o-tetrahydropyranyloxyphenyl)cyclohexanecarboxylicacid (as prepared in Example XV), there is afforded 2-methyl-3- ethyl 4hydroxy-4- (o-hydroxyphenyl)cyclohexanecarboxylic acid, M.P. l9l C.

M max.: 2.82, 3.04, 5.90, 8.06, 10.40, 10.69, 10.92, 13.23 1.

(KBr) NMR (pyr.): 0.67, 0.78, 0.89; 1.42, 1.53; 2.96

EXAMPLE XX Z-methyl-3-ethyl-4-hydroXy-4-(o,p-dihydroxyphenyl)-cyclohexanecarboxylic acid Following the procedure of Example XVIII, butstarting with Z-methyl 3 ethyl 4hydroxy-4-(o,p-bis-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid(as prepared in Example XVII), there is aiforded 2-mehtyl-3- ethyl 4hydroxy-4-(o,p-dihydroxyphenyl)cyclohexanecarboxylic acid, M.P. l69-l71C.

01 max.: 2.85, 2.95, 3.12, 5.90, 8.62, 8.89, 10.21, 11.81,

12.10, 1242 (KBr) NMR (pyr.): 0.72, 0.82, 0.93; 1.40, 1.52; 2.92

EXAMPLE XXI 2-methy1-3 -ethyl-4-hydroxy-4-(o-methoxy-p-hydroxyphenyl)cyclohexanecarboxylic acid Following theprocedure of Example XVIII, but starting with2-methyl-3-ethyl-4-hydroxy-4-(o-methoxy-p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylicacid (as prepared in Example XVI), there is afforded 2-methyl-3- ethyl 4hydroxy-4-(o-methoxy-p-hydroxyphenyl)cyclohexanecarboxylic acid, M.P.128-131 C.

18 max.: 2.95, 5.88, 8.31, 9.65, 10.33, 11.97 1 (KBr) NMR (pyr.): 0.67,0.78, 0.90; 1.46, 1.57; 2.94

EXAMPLE XXII2-methyl-3-ethyl-4-hydroxy-4-(m-acetoxyphenyl)cyclohexanecarboxylic acidTo a solution of 2.0 g. of Z-methyl-3-ethy1-4-hydroxy-4-(m-hydroxyphenyl)cyclohexanecarboxylic acid (as prepared in ExampleXVIII), in 25 ml. of pyridine is added with stirring 3 ml. of aceticanhydride. The solution is maintained at 25 C. for twenty hours and isthen hydrolyzed with ice and water. The oily products are extracted withether. The ether solution is washed with cold dilute hydrochloric acidto remove pyridine and is then extracted with three cold portions of 7%aqueous potassium carbonate with each successive carbonate wash beingimmediately acidified with dilute hydrochloric acid. A tacky precipitatefrom the carbonate solutions is extracted with ether and the combinedether solution is dried and evaporated at 25 C. The residue isrecrystallized from ether to atf ord2-methyl-3-ethy1-4-hydroxy-4-(m-acetoxyphenyl)cyclohexanecarboxylicacid, M.P. 172173 C.

M max.: 2.83, 5.68, 8.30, 9.63, 10.71, 12.73 (KBr) NMR (pyr.): 0.61,0.71, 0.82; 1.44, 1.55; 2.94

EXAMPLE XXIII 2-methyl-3-ethyl-4-hydroxy4 (o-acetoxyphenylcyclohexanecarboxylic acid Following the procedure of Example XXII, butstarting with 2-methyl-3-ethyl-4-hydroxy-4- (o-hydroxyphenylcyclohexanecanboxylic acid (as prepared in Example XIX), theer isalforded2-methyl-3-ethyl-4-hydroxy-4-(o-acetoxyphenyl)cyclohexanecarboxylicacid, M.P. 132133 C.

)\)\ max.: 2.82, 5.72, 5.89, 8.20, 8.48, 13.09 4 (KBr) NM'R (pyr.):0.68, 0.80, 0.91; 1.43, 1.55; 296

EXAMPLE XXIV M max.: 2.85, 5.68, 8.108.40, 9.80, 10.87 1. (KBr) NMR('CDCI 0.64, 0.75, 0.86; 0.99, 1.10; 1.89, 2.59

The o-acetoxyphenyl-hydroxy acids prepared according to Examples XXIIIand XXIV are unstable and begin to decompose after a few days at 25 C.They are fully decomposed within two to three weeks at 25 C. thedecomposition follows the route:

OH O O OH CX i OHaCOz CzHs CH3 C 115 II Compounds I and II are mixturesof the A and A isomers.

EXAMPLE XXV 2-methyl-3-ethy1-4-hydroxy-4-(m-chlorophenyl)cyclohexanecarboxylic acid The Grignard reagent from 0.32 mole ofm-chlorobromobenzene, prepared in a mixture of ether andtetrahydrofuran, is stirred at -40 and to it is added 0.1 mole of2-methyl-3-ethyl-4-ketocyclohexanecarboxylic acid in 40 ml. oftetrahydrofuran. This reaction mixture is stirred vigorously and heatedat the reflux tempera-ture for two hours and then it is cooled in iceand hydrolyzed with 400 ml. of saturated aqueous ammonium acetate. Afterfiltration to remove magnesium, the layers are separated and the organicphase is dried and evaporated to a tacky, semi-crystalline residue.Recrystallization from ether or nitromethane affords 9.0 g. of2-methyl-3-ethyl-4-hydroxy- 4 (m chlorophenyl)cyclohexanecarboxylicacid, M.P. 166169 C.

M max.: 2.83, 5.89, 8.01, 12.77, 13.79 (KBr) NMR (pyr.): 0.59, 0.70,0.80; 1.40, 1.52; 2.92

The alkyl esters of the compounds of the invention are prepared bytreatment of metal salts of the hydroxyacids with an appropriate dialkylsulfate.

EXAMPLE XXVI Methyl2-methyl-3-ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate .formamide.The residue of about 1520 ml. is shaken with ether and water, and theether solution is washed with cold 5% sodium hydroxide, followed by fourportions of water. The ether solution is dried and evaporated to aresidue. The residue is recrystallized from hexane to afford methyl 2methyl 3-ethyl-4-hydroxy-4-phenylcyclo hexanecarboxylate, M.P. 112113 C.

M max.: 2.87, 5.79, 8.21, 8.55, 13.29, 14.30,u (KBr) Calcd. for C H O(percent): C, 73.88; H, 8.75. Found (percent): C, 74.00; H, 8.76.

EXAMPLE XXVII Methyl2-methyl-3-ethyl-4-hydroxy-4-(p-trifluoromethylphenylcyclohexanecarboxylate Following the procedure of Example XXVI, butstarting with 2-methyl 3-ethyl 4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylic acid, there is affordedmethyl 2 methyl 3 ethyl 4hydroxy-4-(p-trifiuoromethylphenyl)cyclohexanecarboxylate, M.P. 112- 113C.

M max.: 2.89, 5.88, 7.49, 7.82, 8.61, 8.90, 9.29, 9.84,

11.81, 12.04pt (KBr) Calcd. for C H O F (percent): C, 62.79; H, 6.73.

Found (percent): C, 63.07; H, 6.73.

EXAMPLE XXVIII Methyl2-methyl-3-ethyl-4-hydroxy-4-(m-trifiuoromethylphenyl)cyclohexanecarboxylate Following the procedure of Example XXVI, butstarting with 2-methy1 3-ethyl 4-hydroxy4-(m-trifiuoromethylphenyl)cyclohexanecarboxylic acid, there is affordedmethyl 2-methyl-3-ethyl-4 hydroxy-4(m-trifluoromethylphenyl)cyclohexanecarboxylate, M.P. 122- 124 C.

Mmaxn 2.87, 5.80, 7.50, 8.61, 8.87, 9.24, 12.50, 14.17;].

(KBr) Calcd. for C gH OgF (percent): C, 62.79; H, 6.73.

Found (percent): C, 62.67; H, 6.73.

Following the procedure of Example XXVI by the selection of theappropriate hydroxy acid and dialkyl sulfate, there are prepared:

ethyl 2-methyl-3-ethyl-4'hydroxy-4-benzylcyclohexanecarboxylate,

propyl 2-methyl-3-propyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2-ethyl-3-methyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

What is claimed is: 1. A compound of the formula -oooR Ar I wherein R isselected from the group consisting of hydrogen and lower alkyl of up to8 carbon atoms, R is selected from the group consisting of lower alkylof up to 6 carbon atoms and Ar is selected from the group consisting ofwherein R is selected from the group consisting of hydrogen and hydroxy,R is selected from the group consisting of hydrogen, hydroxy and loweralkyl of up to 4 carbon atoms, chlorine and trifiuoromethyl and R ishydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, diethylamino andwherein at least 1 and not more than 2 of R R and R is hydrogen and atleast one of R R and R is other than hydroxy; a-naphthyl or ,B-naphthyl.

2. A compound of the formula wherein R is selected from the groupconsisting of hydrogen and lower alkyl of up to 8 carbon atoms, R isselected from the group consisting of lower alkyl of up to 6 carbonatoms, R is selected from the group consisting of hydrogen, and loweralkyl of up to 4 carbon atoms, R is selected from the group consistingof hydrogen, lower alkyl of up to 4 carbon atoms, chlorine andtrifluoromethyl and R is selected from the group consisting of hydrogen,lower alkyl of up to 4 carbon atoms, diethylaminoethoxy,trifluoromethyl, and dimethylamino and wherein at least one and not morethan two of R R and R is hydrogen.

3. Z-methyl 3-ethyl 4-hydroxy-4-(p tolyl)cyclohexanecarboxylic acidaccording to claim 2.

4. 2-methyl 3-ethyl 4-hydroxy 4-(m-tolyl)cyclohexanecarboxylic acidaccording to claim 2.

5. Z-methyl 3-ethyl 4-hydroxy4-(p-diethylaminoethoxyphenyl)cyclohexanecarboxylic acid according toclaim 2.

6. 2-methyl 3-ethyl 4-hydroxy4-(p-trifluoromethylphenyl)cyclohexanecarboxylic acid according to claim2 7. Z-methyl 3-ethyl 4-hydroxy4-(m-trifluoromethylphenyl)cyclohexanecarboxylic acid according to claim2.

8. 2-methyl 3-ethyl 4-hydroxy 4-(m-chlorophenyl)-cyclohexanecarboxylicacid according to claim 2.

9. Z-methyl 3-ethyl 4-hydroxy 4-(a-naphthyl)cyclohexanecarboxylic acid.

10. 2-methyl 3-ethyl 4-hydroxy 4-(fl-naphthyl)cyclohexanecarboxylicacid.

References Cited Nathan, et al.: Journ. Amer. Chem. Soc. vol. 78 (1956)pp. 6163-66.

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner US.Cl. X.R.

Patent No.

Inventofls) PIS-1050 4 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION 3, 5 7,77 Dated March 2, 19 1 George Karmas It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

EDWARD M.FIETCHER,JR. Attesting Officer The filing; date should readAugust 22, 1967. I: Collmn 2, line 2! E-et'nyl' should read --3ethyl-.Column 2, line 29, "hydroxy" is misspelled. Column 2, line 61, "diluted"is misspelled. In C! 3, line 65, delete "11.85". Column 3, line 69,insert --c-- befo: 67.00". In Column l, line 56, "methyl" is misspelled.I11 Cola 5, line 31, "there" is fnisspelled. In Column 5, line 35, "296"should read --2.96--. In Column 6, line 35, "c should read c .I,--.Column 6, line 50, "H should read --H In the abstl'ct, "arcyl" shoulread --acy1--.

Signed and sealed this 13th day of July 1971 (SEAL) Attest:

WILLIAM E. SCHUYLER, J Commissioner of Patent

